Mechanisms of early metastatic spread: Epigenetic plasticity and selection of advantageous genotypes

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Analysing the Balb/NeuT mouse model of breast cancer, we found that metastatic dissemination of cancer cells takes place shortly after malignant transformation. Already one to four 4 weeks after induction of the transgene, we detected disseminated tumour cells (DTC) in lung and bone marrow. Surprisingly, DTCs were found in bone marrow before macroscopic or microscopic tumours were detectable. No increase of DTCs in bone marrow was observed with increasing size of the primary tumours neither in mice nor in patients. First molecular studies revealed an upregulation of proteolytic enzymes and of the transcription factor Twist in early lesions that even exceeded the levels detectable in the invasion front of large carcinomas. In the proposed project we want to use the Balb/NeuT model and four other mouse models of our collaborators to identify the molecular mechanisms of early cancer spread. Candidate regulators will be tested on human samples. Central to our project is the attempt to precisely identify the invading and disseminating tumour cells and to provide a detailed description of their phenotype and genotype. Functional assays will test candidate regulators. We will also ask whether the physiological mechanisms of cancer spread seen in sporadically arising tumours are different to currently proposed mechanisms mostly identified in cell lines, which imply that metastatic dissemination is a late event.